An effective vaccine is needed for prevention of HIV-1 transmission. This proposal will test in the SIV-rhesus macaque model of HIV-1 transmission to women the concept that extraordinarily large numbers of SIV-specific CTLs generated by a novel heterologous prime-boost strategy can confer protection by eliminating small founder populations of infected cells at the portal of entry. Flow cytometric and in situ methods of in situ tetramer staining and hybridization will be used to document at relevant tissue sites the large numbers of virus specific CD8 T cells and their interactions with SIV-infected cells. Success of this strategy should enable vaccine design. An effective vaccine to prevent HIV-1 is urgently needed. In this proposal a novel approach to developing such a vaccine is described with tests of its efficacy in the SIV-rhesus macaque model of HIV-1 transmission to women.